The complex cellular and molecular interactions that function pathogenically in human synovial inflammatory diseases such as rheumatoid arthritis remain only partially understood. We have recently demonstrated a previously unappreciated critical role for the leukotriene lipid mediators of inflammation in the K/BxN serum transfer model of inflammatory arthritis. Furthermore, we find that the critical leukotriene species for arthritis induction is LTB4 and that neutrophils are an important source of this arthritogenic LTB4. These findings identify an important effector function for the neutrophil lineage in this model of inflammatory arthritis. In this proposal, we will investigate the response of the synovial mesenchyme and synovial fibroblasts in particular to LTB4. In specific, the aims of this proposal will define the breadth of inflammatory effector functions elicited in synovial fibroblasts by LTB4 in mouse and man (Aims 1,3). Furthermore, we will define the role of specific LTB4 receptors in engendering these effector responses. We will gain further mechanistic insight into regulation of LTB4 receptor function by examining the role of barrestins and G-protein receptor kinases (GRKs) in modulating LTB4-induced effector functions in synovial fibroblasts (Aim 2). Finally, we will extend our in vitro analyses by examining the role of LTB4 and specific LTB4 receptors in regulating the synovial mesenchyme response in vivo (Aim 4). Thus, this proposal will utilize both in vitro cellular and molecular techniques and in vivo genetic approaches to define mechanisms by which LTB4 participates in synovial tissue inflammation. These analyses will shed light on pathogenic mechanisms relevant to human inflammatory arthritis such as rheumatoid arthritis. It is likely that further understanding of synovial LTB4 participation in inflammatory arthritis will shed light on pathogenic mechanisms directly relevant to human inflammatory arthritis (e.g., rheumatoid arthritis) and open new avenues of treatment for these diseases. Furthermore, these studies will expand our understanding of eicosanoid biology in inflammatory responses.